FASgen, Inc. is developing novel small molecules to treat markedly obese individuals (BMI 32-39), who are at high risk for obesity-associated conditions such as Type II diabetes, hypertension and coronary artery disease. The first compound tested, FAS3075, mediates weight loss via two distinct mechanisms: 1) Reduced appetite and diminished food intake, caused by inhibition of fatty acid synthase (FAS) in the hypothalamus and consequent modulation of hypothalamic neuropeptides that control feeding behavior; 2) Increased energy expenditure in peripheral tissues, caused by stimulation of the carnitine O-palmitoyltransferase- 1 (CPT-1) pathway for fatty acid oxidation. Candidate compounds will be tested for ability to inhibit FAS and/or stimulate CPT-1 in vitro. Active compounds that are cytotoxic to cultured human fibroblasts or rat neurons, or mutagenic in an Ames test, will be eliminated. Compounds that meet in vitro screening criteria will be tested in a murine model of diet-induced obesity to select those that a) are orally active, b) induce at least 5% weight loss within 7 days after a single dose of no more than 100 mg/kg; and c) are reversible, as judged by recovery of normal weight in both obese and lean mice within 30 days following treatment. Within each pharmacologic class (FAS inhibitor, CPT-1 stimulator, or dual acting), the compound having the largest therapeutic window will be designated as the series lead. SBIR Phase II goals will be to make a final selection of lead compound based on chronic dosing in an additional animal model of diet-induced obesity, complete the preclinical data package needed to file an IND with FDA, and initiate clinical trials for proof of principle in man.